Chronic kidney disease (CKD) is a public health epidemic that increases risks of end-stage renal disease (ESRD), cardiovascular disease (CVD) and death. Existing therapies for CKD improve outcomes only modestly. Therapeutic strategies that target novel CKD-specific mechanisms of CVD and CKD progression are desperately needed to improve health. Disordered mineral metabolism is a nearly universal complication of CKD, regardless of its underlying etiology. An elevated level of fibroblast growth factor 23 (FGF23) is the earliest manifestation of disordered mineral metabolism in CKD. FGF23 rises in response to high phosphate diets and in states of impaired phosphate excretion, such as CKD. Rising FGF23 in CKD maintains normal serum phosphate, but also inhibits renal calcitriol production, which causes secondary hyperparathyroidism, and reduces klotho expression, which accelerates arterial calcification. Elevated FGF23 powerfully predicts ESRD, CVD events and death, and data from our group, validated by new preliminary data, suggest potential underlying pathogenic mechanisms: FGF23 induces left ventricular hypertrophy and accelerates CKD progression, and phosphate excess and klotho deficiency induce arterial calcification independent of FGF23. Based on these data, FGF23 excess and disordered mineral metabolism are leading candidates to target in an outcomes trial. Our long-term goal is to prove by randomized trial that treatment of FGF23 excess and disordered mineral metabolism with phosphate binders, dietary phosphate manipulation, and active vitamin D, will reduce risks of ESRD, CVD events and death in CKD stages 3-4. In this Clinical Center application, we propose two pilot studies to fill remaining knowledge gaps that will inform the design of an outcomes trial. In Pilot Study 1, we will conduct a 6-month, randomized, 3 x 2 study of 150 CKD stage 3-4 patients of lanthanum versus sevelamer versus. placebo, alone and combined with dietary phosphate manipulation to compare their effects on FGF23, phosphate and other mineral metabolites. The results will define which binder should be advanced to an outcomes trial, and whether it should be accompanied by a dietary intervention. In Pilot Study 2, we will conduct a 12-month, randomized, 2 x 2 study of the winning phosphate binder + diet arm in Pilot Study 1 versus placebo, and calcitriol vs. placebo in 220 CKD stage 3-4 patients to test the hypothesis that combining active therapies will synergistically improve surrogate markers of CVD and renal risk. A decade of work in the field and extensive preliminary data support our hypotheses. Our team has the requisite clinical research expertise in FGF23 and vitamin D to complete these studies. The University of Miami has a track record of recruiting minority participants in multi-center trials, which is critical in diseases that disproportionately affect minorities, such as CKD. Backed by a strong institutional environment energized by a new CTSA award, our participation in the U01 Consortium will enrich the diversity of study populations it recruits and allow us to contribute to the collaborative effort aimed at improving dismal clinical outcomes suffered by millions of patients with CKD.